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Macrovascular Residual Risk THROUGH LANDMARK STUDY

1 April 2009
In statin-treated patients, the magnitude of cardiovascular risk reduction depends on the decrease in LDL-C achieved: results of a meta-analysis

Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78.

Cholesterol Treatment Trialists
Summary
Comments & References
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STUDY SUMMARY
Objective: To evaluate the outcomes of previous trials on statin therapy.
Study population:
90 056 patients with a history of coronary heart disease (CHD), diabetes and/or hypertension, who were administered statins in 14 randomised trials.
Primary endpoint:
All-cause, CHD and non-CHD mortality.
Secondary endpoint:
Effects on CHD death and major disease and cardiovascular events.
Study design & method
Meta-analysis of original randomised trials.
Main results:
  • 12% proportional reduction in all-cause mortality per 1.0 mmol/L (39 mg/dl) reduction in LDL-cholesterol (LDL-C) reflecting a significant 19% reduction in coronary mortality (p<0.0001).
  • Significant reductions in all cardiovascular events.
Author's conclusion: 5-year incidence of major coronary events, coronary revascularisation, and stroke was reduced by about 1/5th per mmol/L reduction in LDL-C, largely irrespective of the initial lipid profile or other presenting characteristics. The absolute benefit related chiefly to an individual’s absolute risk of such events and to the achieved absolute reduction in LDL-C.

COMMENT

In 1994, a decision was made to undertake periodic systematic meta-analyses of relevant large-scale randomized trials
of lipid modifying treatments in order to clarify the effects on coronary death or on other vascular or non-vascular outcomes.1
The meta-analysis of the Cholesterol Treatment Trialists’ (CTT)1 assessed clinical outcome in each trial weighted by the absolute LDL-C difference in that trial at the end of the first year of follow-up. The results were reported as the effects per 1.0 mmol/L (39 mg/dL) reduction in LDL-C. The results showed that overall the weighted mean difference in LDL-C at 1 year was 1.09 mmol/L (42 mg/dL).

Linear relationship between reduction in major vascular events and absolute reduction in LDL-C
During a mean 5-year follow-up there was a 12% proportional reduction in all-cause mortality per mmol/L reduction in LDL-C (rate ratio [RR] 0.88, 95% CI: 0.84-0.91; p <0·0001). This reflected a significant 19% relative reduction in coronary mortality (0.81, 0.76-0.85; p <0·0001), and non-significant reductions in non-coronary vascular mortality and non-vascular mortality. Corresponding significant reductions (p <0.0001) in myocardial infarction or coronary death, the need for coronary revascularization and fatal or non-fatal stroke were observed, and combining these, an overall 21% reduction in any major vascular event.

The proportional reduction in major vascular events differed significantly (p <0·0001) according to the absolute reduction in LDL-C achieved, with an approximately linear relationship (Figure 1). The results suggest that instead of lowering LDL-C to absolute cut-off target levels, it may be a sensible approach to also aim for absolute reduction in LDL-C for risk reduction. They also suggest that the bulk of the cardiovascular benefits of statins are strictly dependent on their LDL-C -lowering effects.

Reduction in LDL-C translated into a risk reduction for patients with pre-existing CHD
The overall reduction in CHD mortality of about 1/5th per mmol/L LDL-cholesterol reduction translated into 48 (95% CI: 39, 57) fewer patients having major vascular events per 1000 among those with pre-existing CHD at baseline, compared with 25 (CI: 19, 31) per 1000 among participants with no such history.

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Figure 1: Relation between proportional reduction in incidence of major coronary events (a) and major vascular events (b)
and mean absolute LDL-cholesterol reduction at 1 year. Square represents a single trial plotted against
mean absolute LDL-cholesterol reduction at 1 year, with vertical lines above and below corresponding to one SE
of unweighted event rate reduction. Trials are plotted in order of magnitude of difference in LDL-cholesterol difference at 1 year.
For each outcome, regression line (which is forced to pass through the origin) represents weighted event rate reduction per mmol/L
LDL-cholesterol reduction.

References
  1. Cholesterol Treatment Trialists’ (CTT) Collaboration. Am J Cardiol 1995;75:1130–34.
  2. Tobert JA. Nat Rev Drug Discov 2003; 2: 517–26.
Key words Absolute LDL-cholesterol reduction – reduction of major cardiovascular events